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A New High Penetrant Intronic Pathogenic Variant Related to Long QT Syndrome Type 2.

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A newly identified KCNH2 splice site variant, c.77-2del, is pathogenic for Long QT Syndrome type 2. This finding highlights the importance of investigating splice site variants for improved genetic counseling and clinical management of cardiac channelopathies.

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Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Medicine

Background:

  • Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy caused by KCNH2 gene variants.
  • Pathogenic variants, particularly splice site mutations, disrupt cardiac repolarization, increasing arrhythmia and sudden cardiac death (SCD) risk.
  • Genotype-phenotype correlations are crucial due to variable clinical expressivity, even within families.

Purpose of the Study:

  • To identify and characterize new pathogenic KCNH2 variants.
  • To analyze genotype-phenotype correlations in families with LQT2.
  • To evaluate the clinical significance of novel splice site variants.

Main Methods:

  • Next-generation sequencing (NGS) of 210 cardiovascular genes in 390 LQTS patients.
  • Genetic and clinical data collection from index cases and family members.
  • Segregation analysis to confirm variant pathogenicity.

Main Results:

  • Identified 12 carriers of the novel KCNH2 c.77-2del splice site variant.
  • Segregation analysis confirmed high penetrance, supporting pathogenicity.
  • Previous KCNH2 p.Ser261fs variant also analyzed.

Conclusions:

  • The KCNH2 c.77-2del variant is pathogenic for LQT2.
  • Further research on splice site variants is essential for clinical management and genetic counseling.
  • Understanding genotype-phenotype relationships improves care for LQT2 patients.